TORNA ALL’ELENCO

Benefit of circulating methylated biomarkers inclusion in the management of metastatic colorectal cancer patients in United European Gastroenterology Journal

2017
AOU Città della Salute di Torino

Tipo pubblicazione

Conference Abstract

Autori/Collaboratori (28)Vedi tutti...

Barault L

Amatu A

Siravegna G


et alii...

Abstract

Introduction: Current guidelines for the management of patients with metastatic colorectal cancer (mCRC) advise a bimonthly treatment response evaluation 1. However, growing evidence demonstrated that early tumour shrinkage is associated with long-term outcome 2,3. Cell-free circulating DNA (cfDNA) assessment offers a highly specific and minimally invasive method amenable on regular basis to patients, but is currently impaired by the lack of consensus markers 4. Early alterations in methylation patterns are highly prevalent and limited to specific regions of the genome, allowing for a universal assay design compatible for population studies. Aims & Methods: We aimed to identify an optimal panel of cancer specific biomarkers for the purpose of monitoring therapeutic outcome in cfDNA in mCRC patients. Comparison of genome-wide DNA methylation profiles of a collection of 149 CRC cell lines with normal mucosa and blood cells identified five genes (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC) to be used as universal liquid biopsy assay for mCRC. Markers were validated in silico using methylome data from CRC specimens. Digital PCR-based assays were then designed and performed in tissue (N=112) and cfDNA samples from mCRC patients (N=182) and self-declared healthy donors (N=50). Retrospective longitudinal assessment of the panel was performed and compared to current gold standards (imaging, CEA). Results: Average methylation (and range) was 2.3% [0.2-8.4] and 55.2% [20.2-94.9] for normal tissues and for macro-dissected matched tumour tissues respectively (p=0.001). Using cfDNA individual markers easily stratified self-declared healthy donor from mCRC patients samples (average specificity: 0.96; average specificity: 0.69). Male gender was significantly associated with lower methylation values (p=0.023), while the presence of unresected primary tumour (p=0.002), bulky disease (defined as massive tumour involvement of 450% of liver or lungs; p=0.012) or multiple metastatic le

DOI : 10.1177/2397847317743186

Keywords

alpha4 integrin; B Raf kinase; biological marker; endogenous compound; epidermal growth factor receptor; glutamate receptor 4; K ras protein; mitogen activated protein kinase kinase kinase; panitumumab; regorafenib; temozolomide; adult; blood cell; cancer patient; cancer size; cancer survival; cell line; chemotherapy; clinical trial; controlled clinical trial; controlled study; DNA methylation; drug therapy; female; gender; gene amplification; gene mutation; genetic marker; gold standard; human; human cell; human tissue; liquid biopsy; liver; lung; major clinical study; male; metastatic colorectal cancer; mucosa; polymerase chain reaction; population research; primary tumor; progression free survival;